rs762979130

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_004826.4(ECEL1):​c.2151+2T>G variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)

Consequence

ECEL1
NM_004826.4 splice_donor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.26
Variant links:
Genes affected
ECEL1 (HGNC:3147): (endothelin converting enzyme like 1) This gene encodes a member of the M13 family of endopeptidases. Members of this family are zinc-containing type II integral-membrane proteins that are important regulators of neuropeptide and peptide hormone activity. Mutations in this gene are associated with autosomal recessive distal arthrogryposis, type 5D. This gene has multiple pseudogenes on chromosome 2. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.041237112 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ECEL1NM_004826.4 linkc.2151+2T>G splice_donor_variant, intron_variant Intron 16 of 17 ENST00000304546.6 NP_004817.2 O95672-1A0A6F7YIA8
ECEL1NM_001290787.2 linkc.2145+2T>G splice_donor_variant, intron_variant Intron 16 of 17 NP_001277716.1 O95672-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ECEL1ENST00000304546.6 linkc.2151+2T>G splice_donor_variant, intron_variant Intron 16 of 17 1 NM_004826.4 ENSP00000302051.1 O95672-1
ECEL1ENST00000409941.1 linkc.2145+2T>G splice_donor_variant, intron_variant Intron 15 of 16 1 ENSP00000386333.1 O95672-2
ECEL1ENST00000411860.5 linkc.330+2T>G splice_donor_variant, intron_variant Intron 4 of 5 3 ENSP00000412683.1 H7C3M0
ECEL1ENST00000482346.1 linkn.2462+2T>G splice_donor_variant, intron_variant Intron 15 of 16 2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
33
DANN
Uncertain
0.99
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
4.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.96
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.96
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233345426; API